chr3-165188246-T-G

Variant names:

• chr3-165188246-T-G
• rs377258565
• NM_001318810.2:c.2585A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001318810.2(SLITRK3):​c.2585A>C​(p.His862Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLITRK3 NM_001318810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223

Genes affected

SLITRK3 (HGNC:23501): (SLIT and NTRK like family member 3) This gene encodes a member of the Slitrk family of structurally related transmembrane proteins that are involved in controlling neurite outgrowth. The encoded protein contains two leucine-rich repeat (LRR) domains and a C-terminal domain that is partially similar to Trk neurotrophin receptor protein. Enhanced expression of this gene was found in tissue from several different types of tumors. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15914756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK3	NM_001318810.2	c.2585A>C	p.His862Pro	missense_variant	Exon 2 of 2	ENST00000475390.2	NP_001305739.1
SLITRK3	NM_001318811.2	c.2585A>C	p.His862Pro	missense_variant	Exon 2 of 2		NP_001305740.1
SLITRK3	NM_014926.4	c.2585A>C	p.His862Pro	missense_variant	Exon 2 of 2		NP_055741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK3	ENST00000475390.2	c.2585A>C	p.His862Pro	missense_variant	Exon 2 of 2	1	NM_001318810.2	ENSP00000420091.1
SLITRK3	ENST00000241274.3	c.2585A>C	p.His862Pro	missense_variant	Exon 2 of 2	1		ENSP00000241274.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2585A>C (p.H862P) alteration is located in exon 2 (coding exon 1) of the SLITRK3 gene. This alteration results from a A to C substitution at nucleotide position 2585, causing the histidine (H) at amino acid position 862 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.51	.;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.0	B;B
Vest4		0.22
MutPred		0.28		Gain of methylation at K865 (P = 0.1039);Gain of methylation at K865 (P = 0.1039);
MVP		0.31
MPC		0.31
ClinPred		0.22	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377258565; hg19: chr3-164906034;